Red blood cell (RBC) transfusion management includes the criteria used to determine when transfusion should occur in preterm infants. There is controversy regarding whether more restrictive or more liberal criteria would best serve the goal of optimal brain development. Although some studies have indicated that liberal transfusions may be neuroprotective, our findings from the previous 4 years of this PPG indicate that liberal transfusions result in poor long-term brain development, and this is particularly true for females. The overall aim of Project #3 is to evaluate the neurodevelopmental outcomes of differential transfusion practices from a mechanistic viewpoint. We hypothesize that liberal transfusion will result in poorer neurodevelopmental outcomes compared to restrictive transfusion practices. Potential mechanisms explored for this phenomenon include inflammation and/or erythropoietin (Epo) suppression that result from liberal RBC transfusion. Cerebral white matter and sex effects will be of particular interest. Specific Aim 1 will be to measure the relationships between serum biomarkers (average hematocrit (HCT), iron, ferritin, c-reactive proteins, cytokines and Epo), and brain structure (using MRI) in preterm infants that are randomized to either restricted or liberal transfusion. Biomarkers and MRI scan will be obtained during the NICU stay. Specific Aim 2 will examine the effects of differential transfusion on brain development using a longitudinal assessment of the same infants at 12 months and 24 months. Follow-up assessments will include a comprehensive battery of cognitive and developmental measures as well as a follow-up MRI scan. The current proposal is designed to 'extend' an NICHD Neonatal Research Network trial to evaluate the relationship between neonatal transfusion approach and neurodevelopmental outcome. This study is called the Impact of a Liberal Red Blood Cell Transfusion Strategy on Neurologically-lntact Survival of Extremely- Low-Birth-Weight Infants: The Transfusion and Brain Injury (TABI) Trial. The TABI protocol will be the foundation for recruitment of subjects, our current proposal would extend the TABI by: 1) assessing transfusion status and neurodevelopmental impairment (NDI) as continuous measures rather than dichotomous measures; 2) use additional assessments that more sensitively and more specifically quantify brain structure and function; and 3) explore specific proposed mechanisms by which differential transfusion may impact brain development (inflammation and Epo suppression).